The aim of this study was to investigate in a longitudinal approach whether levothyroxine (LT4) substitution has a different impact on quality of life (QoL) and thyroid related QoL in younger (<40 years) and older subjects (>60 years) with elevated thyroid-stimulating hormone (TSH) concentrations. The study included male and female patients with newly diagnosed, untreated subclinical hypothyroidism defined by TSH>8 mU/l. Patients were recruited throughout Germany from 2013–2016 and evaluated by clinical assessment, blood sampling and questionnaires for health related QoL and thyroid-disease thyroid-related QoL (ThyPRO) at time of diagnosis and six months after initiation of LT4 treatment. We found significantly lower QoL in both young and old patients with subclinical hypothyroidism compared to age-matched healthy individuals. Higher scores on follow-up were found in all patients irrespective of age, indicating better QoL on LT4 therapy. Analysis of the ThyPRO questionnaire showed that old patients experienced less Emotional Susceptibility, Tiredness, and Impaired Day Life on LT4, while young patients reported less Cognitive Complaints, Emotional Susceptibility, and Impaired Day Life compared to baseline assessment. Hypothyroidism with TSH concentrations>8 mU/l is associated with impairment in general and ThyPRO QoL in young and old age. Older patients benefited from LT4 therapy and remarkably show similar degree of improvement as younger patients, albeit with some thematic variation in ThyPRO QoL. Our data confirm current recommendations on initiation of LT4 substitution and suggest that this should not be withheld in elderly with TSH concentration above 8–10 mU/l.

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

Background Hypothyroidism impairs cardiovascular health and contributes to endothelial dysfunction with reduced vasodilation. How triiodothyronine (T3) and its receptors are involved in the regulation of vasomotion is not yet fully understood. In general, thyroid hormone receptors (TRs) either influence gene expression (canonical action) or rapidly activate intracellular signaling pathways (noncanonical action). Here we aimed to characterize the T3 action underlying the mechanism of arterial vasodilation and blood pressure regulation. Methods Mesenteric arteries were isolated from male rats, wildtype (WT) mice, TRα knockout (TRα 0) mice and from knock-in mice with a mutation in the DNA-binding domain (TRα GS). In this mutant, DNA-binding and, thus, canonical action is abrogated while noncanonical signaling is preserved. In a wire myograph system, the isolated vessels were pre-constricted with norepinephrine. The response to T3 was measured, and the resulting vasodilation (Δ force [mN]) was normalized to maximum contraction with norepinephrine and expressed as percent vasodilation after maximal pre-constriction with norepinephrine (% NE). Isolated vessels were treated with T3 (1x10 -15 to 1x10 -5 mol/L) alone and in combination with the endothelial NO-synthase (eNOS) inhibitor L-NG-Nitroarginine methyl ester (L-NAME) or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The endothelium was removed to determine the contribution of T3 to endothelium-dependent vasodilation. The physiological relevance of T3-induced vasodilation was determined by in vivo arterial blood pressure measurements in male and female mice. Results T3 treatment induced vasodilation of mesenteric arteries from WT mice within 2 minutes (by 21.5±1.7% NE). This effect was absent in arteries from TRα 0 mice (by 5.3±0.6% NE, P&lt;0.0001 vs. WT) but preserved in TRαGS arteries (by 17.2±1.1% NE, n.s. vs. WT). Inhibition of either eNOS or PI3K reduced T3-mediated vasodilation from 52.7±4.5% NE to 28.5±4.1% NE and 22.7±2.9% NE, respectively. Removal of the endothelium abolished the T3-mediated vasodilation in rat mesenteric arteries (by 36.7±5.4% NE vs. 3.5±6.2% NE). In vivo, T3 injection led to a rapid decrease of arterial blood pressure in WT (by 13.9±1.9 mmHg) and TRαGS mice (by 12.4±1.9 mmHg), but not in TRα0 mice (by 4.1±1.9 mmHg). Conclusions These results demonstrate that T3 acting through noncanonical TRa action impacts cardiovascular physiology by inducing endothelium-dependent vasodilation within minutes via PI3K and eNOS activation.

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Context 3,5,3'-L-triiodothyronine (T3) is a potent inducer of hepatocyte proliferation via the Wnt/β-catenin signaling pathway. Previous studies suggested the involvement of rapid noncanonical thyroid hormone receptor (TR)β signaling, directly activating hepatic Wnt/β-catenin signaling independent from TRβ DNA binding. However, the mechanism by which T3 increases Wnt/β-catenin signaling in hepatocytes has not yet been determined. Objective We aimed to determine whether DNA-binding of TRβ is required for stimulation of hepatocyte proliferation by T3. Methods Wild type (WT) mice, TRβ knockout mice (TRβ KO), TRβ mutant mice with either specifically abrogated DNA-binding (TRβ GS) or abrogated direct PI3K activation (TRβ 147F) were treated with T3 for 6h or 7 days. Hepatocyte proliferation was assessed by Ki67 staining and apoptosis by TUNEL-assay. Activation of β-catenin signaling was measured in primary murine hepatocytes. Gene expression was analyzed by microarray, gene set enrichment analysis (GSEA) and qRT-PCR. Results T3 induced hepatocyte proliferation with an increased number of Ki67-positive cells in WT and TRβ 147F mice (9.2±6.5% and 10.1±2.9%) compared to TRβ KO and TRβ GS mice (1.2±1.1% and 1.5±0.9%). Microarray analysis and GSEA showed that genes of the Wnt/β-catenin pathway, among them Fzd8 (Frizzled receptor 8) and Ctnnb1 (β-catenin), were positively enriched only in T3-treated WT and TRβ 147F mice while anti-proliferative factor Btg2 was repressed. Consequently, expression of Ccnd1 (CyclinD1) was induced. Conclusions Instead of directly activating Wnt signaling, T3 and TRβ induce key genes of the Wnt/β-catenin pathway, ultimately stimulating hepatocyte proliferation via CyclinD1. Thus, canonical transcriptional TRβ action is necessary for T3-mediated stimulation of hepatocyte proliferation.

Age and sex impact prevalence and clinical features of thyroid disease. Thyroid dysfunction occurs with a higher frequency in elderly patients and females. Moreover, age alters clinical presentation of hyper- and hypothyroidism and onset of thyroid hormone (TH) related co-morbidities leading to increased risk for underdiagnosis and maltreatment in the elderly. Rodent models allow further insights into mechanisms of age- and sex-dependent TH action in target tissues. In this review, we summarize findings from mouse studies showing distinct effects of age and sex on systemic versus organ-specific TH action and discuss their wider implication for clinical care.

In animal studies, both in basic science and in toxicological assessment of potential endocrine disruptors, the state of the thyroid hormone (TH) axis is often described and defined exclusively by the concentrations of circulating THs and TSH. Although it is known that the local, organ-specific effects of THs are also substantially regulated by local mechanisms such as TH transmembrane transport and metabolism of TH by deiodinases, such endpoint parameters of the axis are rarely assessed in these experiments. Currently developed in vitro assays utilize the Sandell-Kolthoff reaction, a photometric method of iodide determination, to test the effect of chemicals on iodotyrosine and iodothyronine deiodinases. Furthermore, this technology offers the possibility to determine the iodine content of various sample types (e.g., urine, ex vivo tissue) in a simple way. Here, we measured deiodinase type 1 and iodotyrosine dehalogenase activity by means of the Sandell-Kolthoff reaction in ex vivo samples of hypo- and hyperthyroid mice of two age groups (young; 3 months and old; 20 months). In thyroid, liver and kidney, organ-specific regulation patterns emerged across both age groups, which, based on this pilot study, may serve as a starting point for a deeper characterization of the TH system in relevant studies in the future and support the development of Integrated Approach for Testing and Assessment (IATA).

Hypothyroidism has been shown to reduce infarct size in rats, but the underlying mechanisms are unclear. We used isolated pressure-constant perfused hearts of control, hypothyroid and hyperthyroid mice and measured infarct size, functional parameters and phosphorylation of key molecules in cardioprotective signaling with matched heart rate. Compared with controls, hypothyroidism was cardioprotective, while hyperthyroidism was detrimental with enlarged infarct size. Next, we asked how thyroid hormone receptor α (TRα) affects ischemia/reperfusion (IR) injury. Thus, canonical and noncanonical TRα signaling was investigated in the hearts of (i) mice lacking TRα (TRα0), (ii) with a mutation in TRα DNA-binding domain (TRαGS) and (iii) in hyperthyroid TRα0 (TRα0hyper) and TRαGS mice (TRαGShyper). TRα0 mouse hearts were protected against IR injury. Furthermore, infarct size was reduced in the hearts of TRαGS mice that lack canonical TRα signaling but maintain noncanonical TRα action. Hyperthyroidism did not increase infarct size in TRα0 and TRαGS mouse hearts. These cardioprotective effects were not associated with increased phosphorylation of key proteins of RISK, SAFE and eNOS pathways. In summary, chronic hypothyroidism and the lack of canonical TRα signaling are cardioprotective in IR injury and protection is not due to favorable changes in hemodynamics.